Parkinson Disease: Fox SH

Lim SY, Fox SH, Lang AE. · Movement Disorders Centre, Toronto Western Hospital, 399 Bathurst St, Toronto, Ontario M5T 2S8, Canada. · Arch Neurol. · Pubmed #19204152 No free full text.

Abstract: In recent years, there has been increasing recognition of the features of Parkinson disease that are not related to nigrostriatal dopamine deficiency. This review addresses selected clinical, anatomic, pathologic, and biochemical correlates of the early premotor symptoms of Parkinson disease, later nonmotor fluctuations, and advanced dopa-unresponsive motor and nonmotor features. The recognition of early features that predate classic motor symptoms will be important as effective neuroprotective therapy becomes available. Later-stage features often contribute markedly to disability and impaired quality of life and, therefore, represent an important future therapeutic challenge.

Fox SH, Brotchie JM, Lang AE. · Movement Disorders Clinic, Division of Neurology, University of Toronto, Toronto, ON, Canada. · Lancet Neurol. · Pubmed #18848312 No free full text.

Abstract: Non-dopaminergic treatments are increasingly being recognised as part of the therapeutic armamentarium for Parkinson's disease (PD). Clinical and pathological studies have shown that the disease extends beyond the substantia nigra pars compacta and involves various non-dopaminergic neurotransmitter systems that mediate both motor and non-motor symptoms that characterise PD. To date, several therapeutic strategies have been proposed to treat such symptoms. However, despite the significant morbidity associated with these symptoms, particularly non-motor symptoms, research into and drug development for problems such as mood and autonomic dysfunction remain scarce. Here, we review novel non-dopaminergic approaches that are in at least phase II clinical development for the treatment of PD.

Fox SH, Lang AE. · Division of Neurology, Toronto Western Hospital, Movement Disorders Clinic, University of Toronto, Toronto, Ontario, Canada. · Mov Disord. · Pubmed #18781677 No free full text.

Abstract: Long term levodopa therapy in Parkinson's disease (PD) results in a range of problems. These include fluctuations in FD symptoms termed motor fluctuations, as well as non-motor symptoms, termed non-motor fluctuations. Here we review the phenomenology and methods of assessing these levodopa-related complications.

Fox SH, Chuang R, Brotchie JM. · Movement Disorders Clinic, University of Toronto, Toronto Western Hospital, Toronto, Ontario, Canada. · Prog Brain Res. · Pubmed #18772047 No free full text.

Abstract: Long-term treatment for Parkinson's disease (PD) with the dopamine-precursor levodopa (l-DOPA) results in the development of motor fluctuations, including involuntary movements, termed l-DOPA-induced dyskinesia (LID). Currently, effective treatments for LID are limited. The neurodegenerative processes underlying PD result in loss of serotonin (5-HT) input from the dorsal raphe nucleus (DRN) to the striatum, but to a lesser extent than loss of dopamine input. l-DOPA may be converted to dopamine in remaining serotonergic neurons and the non-physiological release of dopamine may lead to abnormal dopamine receptor stimulation in the striatopallidal pathways and result in the generation of LID. Suppressing the activity of these 5-HT inputs to the striatum via presynaptic 5-HT(1A) agonists may reduce LID. However, to date, studies with 5-HT(1A) agonists have suggested a reduction in LID, but with worsening PD disability. Postsynaptic 5-HT(2A) and 5-HT(2C) receptors in the striatum may modulate dopamine to reduce LID and the atypical antipsychotic, clozapine is effective at reducing LID without worsening PD. Alternatively, postsynaptic 5-HT(1A), presynaptic 5-HT(1B/1D) receptors and 5-HT(2C) receptors may modulate GABA and glutamate release within other basal ganglia nuclei to reduce LID. Thus, 5-HT ligands can modulate basal ganglia function and hence motor function through several receptor subtypes and locations, with potential therapeutic benefit to the motor complications induced by long-term l-DOPA therapy in PD. Future studies are needed to develop 5-HT selective drugs that can reduce LID without affecting the anti-parkinsonian action of l-DOPA.

Voon V, Fox SH. · National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Dr, Bldg 10, Room 5S213, Bethesda, MD 20892-1428, USA. · Arch Neurol. · Pubmed #17698698 links to  free full text

Abstract: A range of behaviors presumed to be related to aberrant or excessive dopaminergic medications are being increasingly recognized in Parkinson disease. These behaviors are linked by their incentive- or reward-based and repetitive natures and include pathological gambling, hypersexuality, compulsive shopping, compulsive eating, hobbyism, and compulsive medication use. Such behaviors can have potentially devastating psychosocial consequences and are often hidden. Whether these behaviors are simply related to dopaminergic medications interacting with an underlying individual vulnerability or whether the primary pathological features of Parkinson disease play a role is not known. We reviewed the literature on these behaviors in Parkinson disease, including definitions, epidemiological and potential pathophysiological features, and management. The study of these behaviors allows not only improved clinical management but also greater insight into a biologically mediated complex behavioral model.

Johnston TH, Fox SH, Brotchie JM. · Toronto Western Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON M5T 2S8, Canada. · Expert Opin Drug Deliv. · Pubmed #16296809 No free full text.

Abstract: Innovative drug delivery in Parkinson's disease (PD) has the potential to reduce or avoid many side effects of current treatment, such as wearing-off type fluctuations, dyskinesia, on-off phenomena or bouts of motor freezing. The traditional orally administered formulations of l-dihydroxyphenylalanine combined with a peripheral aromatic acid decarboxylase inhibitor remain the mainstay of treatments for PD. However, such combination therapies have been further formulated to extend their duration of action by including a catechol-O-methyltransferase inhibitor. Preventing the breakdown of dopamine has also been achieved by monoamine oxidase-B inhibition; this approach now having been formulated for sublingual use (Zelapar, Valeant Pharmaceuticals). An alternative approach bypasses the oral route of administration and instead relies on continuous duodenal infusion (Duodopa, Solvay, NeoPharma AB) for better therapeutic effect. The clinical use of dopamine agonists as antiparkinsonian drugs now incorporates a variety of delivery techniques. For example, apomorphine, which relies on parenteral administration for maximum bioavailability, may be delivered via rectal, intranasal, sublingual and subcutaneous (e.g., Apokyn, Mylan Bertek) routes. Meanwhile, rotigotine and lisuride have both been formulated for delivery via skin patches. Finally, the authors examine more experimental delivery techniques, including the delivery of genes via viral vectors or liposomes, intracranial transplant of a variety of cells and of L-dihydroxyphenylalanine by prodrug-dispensing liposomes or pulmonary delivery (AIR, Alkermes). The advent and application of these varied technologies will help encourage patient-specific means of treatment for PD.

Silverdale MA, Fox SH, Crossman AR, Brotchie JM. · Manchester Movement Disorder Laboratory, Division of Neuroscience, School of Biological Sciences, University of Manchester, Manchester, United Kingdom. · Adv Neurol. · Pubmed #12442686 No free full text.

This publication has no abstract.

Tyne HL, Parsons J, Sinnott A, Fox SH, Fletcher NA, Steiger MJ. · The University of Liverpool, UK. · J Neurol. · Pubmed #15592733 No free full text.

Abstract: OBJECTIVES: Apomorphine is a potent dopamine agonist useful in the treatment of Parkinson's disease patients with disabling motor fluctuations and 'off' periods, not responding to oral medication. It can also be of benefit in reducing dyskinesia by providing more constant dopaminergic stimulation and permitting lower levodopa dosage. However, there is a paucity of information on long-term benefits of apomorphine, including no large-scale phase III trial. We have examined our experience of apomorphine over the last 10 years, to assess indications, pattern of use, efficacy, and side effect profile. METHODS: All patients requiring apomorphine were identified through the Parkinson's disease Nurse Specialist's records. An audit form was produced so that the same information was gathered from all case-notes. RESULTS: There were 107 patients (61 males and 46 females). Mean age of disease onset was 50.9 years, SD+/-9.3 (range 29-78). The mean duration of disease at start of apomorphine treatment was 10 years (SD+/-4.8, range 2-29). The most common indications for apomorphine were severe unpredictable 'off' periods (75.7 %), motor fluctuations (18.7 %) and dyskinesia (5.6 %). Most patients (63.6 %) used both intermittent subcutaneous injections and infusion via pump; 25.2% were on intermittent injection, and 11.2 % infusion alone. Mean dose per injection was 3.7 mg. Mean infusion dose 69.8 mg, running over a mean of 13.5 hours. The mean duration of intermittent apomorphine use was 48.2 months. The mean duration of infusion was 25.1 months. Complications included skin problems in 16 patients, 2 had symptomatic hypotension, 2 worsening confusion, 1 new confusion and 5 new hallucinations (after sometime on apomorphine). Sixteen patients have stopped using apomorphine completely. Thirteen have stopped the pump, but continue on intermittent injections. CONCLUSION: Subcutaneous apomorphine is easy for patients to use, is well tolerated and has a low incidence of side effects, especially confusion.

Sieradzan KA, Fox SH, Hill M, Dick JP, Crossman AR, Brotchie JM. · Department of Neurology, Manchester Royal Infirmary, UK. · Neurology. · Pubmed #11739835 No free full text.

Abstract: The lateral segment of the globus pallidus (GPl) is thought to be overactive in levodopa-induced dyskinesia in PD. Stimulation of cannabinoid receptors in the GPl reduces gamma-aminobutyric acid (GABA) reuptake and enhances GABA transmission and may thus alleviate dyskinesia. In a randomized, double-blind, placebo-controlled, crossover trial (n = 7), the authors demonstrate that the cannabinoid receptor agonist nabilone significantly reduces levodopa-induced dyskinesia in PD.

Nicholas AP, Lubin FD, Hallett PJ, Vattem P, Ravenscroft P, Bezard E, Zhou S, Fox SH, Brotchie JM, Sweatt JD, Standaert DG. · Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, AL 35294-0017, USA. · J Neurochem. · Pubmed #18410512 No free full text.

Abstract: Despite recent advances in the treatment of Parkinson disease (PD), levodopa remains the most effective and widely used therapy. A major limitation to the use of levodopa is the development of abnormal involuntary movements, termed levodopa-induced dyskinesia (LDID), following chronic levodopa treatment. Since recent studies have suggested that modifications of chromatin structure may be responsible for many long-lasting changes in brain function, we have examined post-translational modifications of striatal histones in two models of LDID: an acute murine model and a chronic macaque monkey model, both exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In the primate model, which closely resembles human LDID, we observed that chronic levodopa and the appearance of LDID was associated with marked deacetylation of histone H4, hyperacetylation and dephosphorylation of histone H3, and enhancement of the phosphorylation of extracellular signal-regulated kinase (ERK). In the murine model of acutely rather than chronically induced LDID, dopamine depletion and levodopa treatment also induced deacetylation of histone H4 and phosphorylation of ERK, but histone H3 exhibited decreased trimethylation and reduced rather than enhanced acetylation. These data demonstrate striking changes in striatal histones associated with the induction of LDID in both animal models. The pattern of changes observed, as well as the behavioral features, differed in the two models. However, both models exhibit marked deacetylation of histone H4, suggesting that inhibitors of H4 deacetylation may be useful in preventing or reversing LDID.

de Bie RM, Miyasaki J, Lang AE, Fox SH. · Movement Disorders Centre, Division of Neurology University of Toronto, Toronto, Ontario, Canada. · Can J Neurol Sci. · Pubmed #18062452 No free full text.

Abstract: BACKGROUND: Current Health Canada instructions for use of the dopamine agonists (DA), pramipexole and ropinirole, state that Parkinson's disease (PD) patients should be told not to drive. The objective was to assess neurologists' actual clinical practice concerning driving advice they give to PD patients starting a DA. METHODS: An online survey was created consisting of 4 items regarding demographics, 5 regarding PD and driving, and 9 regarding DA use and driving. The survey was distributed to 563 neurologists. RESULTS: In total 96 neurologists (17.9%) responded. 4.4% tell patients with PD not to drive, solely because they are taking a DA. Respondents assess the patient's tendency for excessive daytime sleepiness and sleep attacks after starting a DA more frequently than after starting other dopaminergic drugs (p < 0.001). DISCUSSION: A minor proportion of the clinicians responding to our survey advise PD patients not to drive, solely because they use a DA. Such being the case, we propose that current Health Canada guidelines need revision.

Zadikoff C, Fox SH, Tang-Wai DF, Thomsen T, de Bie RM, Wadia P, Miyasaki J, Duff-Canning S, Lang AE, Marras C. · Department of Neurology, Northwestern University, Parkinson's Disease and Movement Disorders Center, Chicago, Illinois, USA. · Mov Disord. · Pubmed #18044697 No free full text.

Abstract: Dementia is an important and increasingly recognized problem in Parkinson's disease (PD). The mini-mental state examination (MMSE) often fails to detect early cognitive decline. The Montreal cognitive assessment (MoCA) is a brief tool developed to detect mild cognitive impairment that assesses a broader range of domains frequently affected in PD. The scores on the MMSE and the MoCA were compared in 88 patients with PD. A pronounced ceiling effect was observed with the MMSE but not with the MoCA. The range and standard deviation of scores was larger with the MoCA(7-30, 4.26) than with the MMSE(16-30, 2.55). The percentage of subjects scoring below a cutoff of 26/30 (used by others to detect mild cognitive impairment) was higher on the MoCA (32%) than on the MMSE (11%) (P < 0.000002). Compared to the MMSE, the MoCA may be a more sensitive tool to identify early cognitive impairment in PD.

Thomsen TR, Galpern WR, Asante A, Arenovich T, Fox SH. · Movement Disorders Centre, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada. · Mov Disord. · Pubmed #17876852 No free full text.

Abstract: Sialorrhea is a significant problem in advanced Parkinson's disease (PD). Current treatment options include systemic anticholinergics which frequently cause side effects. We hypothesized that sublingual application of ipratropium bromide spray, an anticholinergic agent that does not cross the blood brain barrier, may reduce drooling without systemic side effects. We performed a randomized, double blind, placebo-controlled, crossover study in 17 subjects with PD and bothersome drooling. Patients were randomized to receive ipratropium bromide or placebo (one to two sprays, maximum of four times per day) for 2 weeks followed by a 1 week washout and crossover for further 2 weeks of treatment. The primary outcome was an objective measure of weight of saliva production. Secondary outcomes were subjective rating of severity and frequency of sialorrhoea using home diaries, United Parkinson's Disease Rating Scale (UPDRS) part II salivation subscore, parkinsonian disability using UPDRS, and adverse events. Ipratropium bromide spray had no significant effect on weight of saliva produced. There was a mild effect of treatment on subjective measures of sialorrhea. There were no significant adverse events. Ipratropium bromide spray was well tolerated in subjects with PD. Although it did not affect objective measures of saliva production, further studies in parkinsonism may be warranted.

Voon V, Thomsen T, Miyasaki JM, de Souza M, Shafro A, Fox SH, Duff-Canning S, Lang AE, Zurowski M. · National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. · Arch Neurol. · Pubmed #17296836 links to  free full text

Abstract: OBJECTIVE: To evaluate factors associated with pathological gambling (PG) in Parkinson disease (PD). DESIGN: Case-control study. SETTING: Outpatient tertiary clinic. Patients Twenty-one patients with idiopathic PD with PG after the patients began receiving medications compared with a consecutive sample of 42 patients with idiopathic PD without compulsive behaviors. MAIN OUTCOME MEASURES: Clinical features, comorbid psychiatric and substance use disorders, personality traits, and impulsivity scores. RESULTS: Patients with PG had a younger age at PD onset (P = .006), higher novelty seeking (P<.001), medication-induced hypomania or mania (P = .001), impaired planning (P = .002), or a personal or immediate family history of alcohol use disorders (P = .002). Novelty seeking, a personal or immediate family history of alcohol use disorders, and younger age at PD onset accurately predicted PG at 83.7% in a logistic regression model, with the model accounting for 62% of the variance. CONCLUSIONS: Patients with PD having a younger age at PD onset, higher novelty seeking traits, and a personal or family history of alcohol use disorders may have a greater risk for PG with dopamine agonists.

Fox SH, Visanji NP, Johnston TH, Gomez-Ramirez J, Voon V, Brotchie JM. · No affiliation provided · Arch Neurol. · Pubmed #16966523 No free full text.

This publication has no abstract.

Gomez-Ramirez J, Johnston TH, Visanji NP, Fox SH, Brotchie JM. · Toronto Western Research Institute, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada. · Mov Disord. · Pubmed #16532454 No free full text.

Abstract: L-dopa-induced dyskinesia (LID) remains a major complication of the treatment of Parkinson's disease. The neural mechanisms underlying LID are thought to involve overactivity of striatal glutamatergic neurotransmission, with resultant underactivation of the output regions of the basal ganglia. Histamine H3 heteroreceptors can reduce glutamate and gamma-aminobutyric acid (GABA) transmission in the striatum and substantia nigra reticulata, respectively. Thus, we tested whether the histamine H3 receptor agonists immepip and imetit can alleviate LID in the MPTP-lesioned marmoset model of Parkinson's disease. Coadministration of immepip (1 mg/kg) with L-dopa (15 mg/kg) was associated with significantly less total dyskinesia than L-dopa alone. When dyskinesia was separately rated as chorea and dystonia, coadministration of L-dopa with either immepip or imetit (both 10 mg/kg) significantly reduced chorea but had no effect on dystonia. The antidyskinetic actions of the H3 agonists were not accompanied by alteration of the antiparkinsonian actions of L-dopa. However, immepip (10 mg/kg), when administered as monotherapy, significantly increased parkinsonian disability compared to vehicle. Overall, the results obtained in this study suggest that histamine H3 receptors may be involved in the neural mechanisms underlying L-dopa-induced dyskinesia in Parkinson's disease.

Johnston TH, Lee J, Gomez-Ramirez J, Fox SH, Brotchie JM. · Toronto Western Research Institute, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada. · Exp Neurol. · Pubmed #15649479 No free full text.

Abstract: l-DOPA-induced dyskinesia (LID) remains a major complication of the treatment of Parkinson's disease (PD). Whilst the MPTP-lesioned primate provides an excellent animal model in which to develop new therapies, however, it is logistically difficult to employ widely. Thus, a simple rodent assay to screen multiple compounds as candidates for further study of their potential in LID would be a valuable addition to the drug development process. Here, we investigate how agents with demonstrated ability to reduce LID in man and monkey can regulate l-DOPA-induced behaviours in the reserpine-treated rat. Administration of l-DOPA (125 mg/kg) to reserpine-treated rats elicited high levels of both horizontal and vertical movement. Drugs that have previously been found to reduce LID in parkinsonian primates and PD patients without compromising the anti-parkinsonian efficacy of l-DOPA selectively and dose-dependently reduce vertical components of activity when co-administered with l-DOPA in the reserpine-treated rat. For instance, amantadine (1 mg/kg) and idazoxan (3 mg/kg) reduced vertical activity by 59% and 83%, respectively, while neither drug had significant effects on horizontal activity. In contrast, haloperidol (1 mg/kg), an agent lacking the ability to selectively reduce LID without compromising the anti-parkinsonian actions of l-DOPA, reduced both horizontal and vertical activity, by 98% and 99%, respectively. We also assessed the actions of an NMDA antagonist, a class of compound proposed to have potential as anti-dyskinetic agents. The effects of MK-801 were dose-dependent (0.01-0.5 mg/kg), at some doses (e.g., 0.05 mg/kg), providing selective reduction of vertical activity (90%), at others (e.g., 0.5 mg/kg), non-selective reduction of vertical and horizontal (99% and 77%, respectively). These observations highlight the association between potential anti-dyskinetic action and a selective reduction in l-DOPA-induced vertical activity in the reserpine-treated rat.

Henry B, Duty S, Fox SH, Crossman AR, Brotchie JM. · Manchester Movement Disorder Laboratory, 1.124 Division of Neuroscience, School of Biological Sciences, Stopford Building, University of Manchester, Oxford Road, M13 9PT, Manchester, UK. · Exp Neurol. · Pubmed #14552886 No free full text.

Abstract: Long-term treatment of Parkinson's disease with levodopa is compromised by the development of motor complications, including on-off fluctuations and involuntary movements termed dyskinesia. The neural mechanisms underlying treatment-related dyskinesias may involve underactivity of the output regions of the basal ganglia, i.e., the medial segment of the globus pallidus (GPm) and substantia nigra pars reticulata (SNR). Increased activity of GABAergic neurons of the "direct" striatopallidal pathway has been implicated in the suppression of the GPm and SNR and thus the development of dyskinesia. The direct pathway uses opioids as a co-neurotransmitter. These opioid peptides are products of the high-molecular weight opioid precursor pre-proenkephalin B (PPE-B). In situ hybridisation studies were employed to investigate PPE-B mRNA expression in postmortem striatal tissue from patients with a clinicopathological diagnosis of Parkinson's disease, all of whom displayed levodopa-induced motor complications, including dyskinesia prior to death and in the caudate-putamen (striatum) of the MPTP-lesioned macaque model of Parkinson's disease with treatment-related dyskinesia. Striatal PPE-B mRNA expression was significantly increased by 172% in dyskinetic Parkinson's disease patients compared to age-matched controls. This increase was heterogeneous with increased expression within the striosomes compared to matrix compartments of the striatum. Striatal PPE-B mRNA expression was significantly increased by 185% in the MPTP-lesioned macaque exhibiting dyskinesia, compared to parkinsonian, nondyskinetic MPTP-lesioned macaques, and by 146% compared to non-parkinsonian, nondyskinetic controls. Increased PPE-B mRNA expression, with subsequent elevations in opioid peptide transmission within the direct striatal output pathways, may underlie treatment-related dyskinesia in Parkinson's disease.

Varma TR, Fox SH, Eldridge PR, Littlechild P, Byrne P, Forster A, Marshall A, Cameron H, McIver K, Fletcher N, Steiger M. · Walton Centre for Neurology and Neurosurgery, Lower Lane, Fazakerley, Liverpool L9 7IJ, UK. · J Neurol Neurosurg Psychiatry. · Pubmed #12531942 links to  free full text

Abstract: OBJECTIVES: To assess the efficacy of bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) in patients with advanced Parkinson's disease previously reliant on apomorphine as their main antiparkinsonian medication. METHODS: Seven patients with motor fluctuations despite optimal medical treatment given as predominantly apomorphine infusion (n=6), or intermittent apomorphine injections (n=1) underwent bilateral STN DBS using frameless stereotactic surgery. Standard assessments of parkinsonism and motor fluctuations, using Unified Parkinson's Disease Rating Scale (UPDRS) were performed before and six months after surgery. Assessments were performed both on and off medication, and postoperative with the stimulators switched on and off. RESULTS: Bilateral STN DBS improved motor scores (UPDRS III) by 61% when off medication (p<0.05). Clinical fluctuations (UPDRS IV items 36-39) were reduced by 46.2% (p<0.05). Total daily apomorphine dose was reduced by 68.9% (p<0.05) and apomorphine infusion via a pump was no longer required in four patients. There were no operative complications. Two patients required treatment for hallucinations postoperatively but there was no significant change in mini-mental state examination. CONCLUSIONS: In patients with advanced Parkinson's disease, previously reliant on apomorphine, bilateral STN DBS is an effective treatment to reduce motor fluctuations and enable a reduction in apomorphine use.

Fox SH, Brotchie JM. · Manchester Movement Disorder Laboratory, School of Biological Sciences, University of Manchester, UK. · Mov Disord. · Pubmed #11104187 No free full text.

Abstract: The involvement of abnormalities in nondopaminergic transmitter systems in Parkinson's disease is noteworthy because of the complications, such as dyskinesia, associated with long-term dopamine replacement therapy. The output regions of the basal ganglia, the substantia nigra pars reticulata, and the medial segment of the globus pallidus are overactive in Parkinson's disease but underactive in dyskinesia. 5-HT2C receptors are localized in these regions and are excitatory. A 5-HT2C receptor binding assay using [3H]-mesulergine and SB 200646A to define nonspecific binding was applied to postmortem tissue from patients with Parkinson's disease and from age-matched control patients. [3H]-mesulergine binding was increased in the substantia nigra pars reticulata by 108% in Parkinson's disease tissue as compared with control tissue. These data suggest abnormalities of 5-HT2C transmission in the basal ganglia of patients with Parkinson's disease.

Nash JE, Fox SH, Henry B, Hill MP, Peggs D, McGuire S, Maneuf Y, Hille C, Brotchie JM, Crossman AR. · Manchester Movement Disorder Laboratory, Room 1.124, Division of Neuroscience, School of Biological Sciences, University of Manchester, Oxford Road, Manchester, M13 9PT, United Kingdom. · Exp Neurol. · Pubmed #10964492 No free full text.

Abstract: Dopamine-replacement strategies form the basis of most symptomatic treatments for Parkinson's disease. However, since long-term dopamine-replacement therapies are characterized by many side effects, most notably dyskinesia, the concept of a nondopaminergic therapy for Parkinson's disease has attracted great interest. To date, it has proved difficult to devise a nondopaminergic therapy with efficacy comparable to that of dopamine replacement. In animal models of Parkinson's disease, loss of striatal dopamine leads to enhanced excitation of striatal NR2B-containing NMDA receptors. This is responsible, in part at least, for generating parkinsonian symptoms. Here we demonstrate that, in the MPTP-lesioned marmoset, monotherapy with the NR2B-selective NMDA receptor antagonist, ifenprodil, administered de novo, has antiparkinsonian effects equivalent to those of l-DOPA (administered as its methyl ester form). In MPTP-lesioned marmosets, median mobility scores, following vehicle-treatment were 12.5/h (range 6-21), compared to 61/h (range 26-121) in normal, non-MPTP-lesioned animals. Following ifenprodil (10 mg/kg) treatment in MPTP-lesioned marmosets, the median mobility score was 66/h (range 34-93), and following l-DOPA (10 mg/kg i.p.) treatment 89/h (range 82-92). The data support the proposal that NR2B-selective NMDA receptor antagonists have potential as a nondopaminergic monotherapy for the treatment of parkinsonian symptoms when given de novo.

Fox SH, Brotchie JM. · School of Biological Sciences, Division of Neuroscience, Manchester Movement Disorder Laboratory, University of Manchester, Room 1.124, Oxford Road, M13 9PT, Manchester, UK. · Eur J Pharmacol. · Pubmed #10856448 No free full text.

Abstract: Non-dopaminergic therapies are of potential interest in the treatment of Parkinson's disease given the complications associated with current dopamine-replacement therapies. In this study we demonstrate that SB 206553 (5-methyl-1-(3-pyridylcarbamoyl)-1,2,3, 5-tetrahydropyrrol[2,3-f]indole) (20 mg/kg) enhanced the actions of the dopamine D(1) receptor agonist, SKF 82958 ((+)-6-chloro-7, 8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide) (1 mg/kg), in eliciting locomotion in the 6-hydroxydopamine-lesioned rat model of Parkinson's disease. This action was only seen following prior priming with L-DOPA (L-3, 4-dihydroxyphenylalanine). SB 206553 had no effect on rotational behaviour when given alone. 5-HT(2C) receptor antagonists may have potential as a means of reducing reliance on dopamine replacement in the treatment of Parkinson's disease.